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Superoxide dismutase (SOD) catalyzes the highly reactive superoxide anion to form hydrogen peroxide, which facilitates cell proliferation and death. We investigated whether red cell SOD (R-SOD) activity is associated with an increased risk of cancer in a Japanese general population. We prospectively analyzed data from 1,921 participants (800 men and 1,121 women; age, 58.7 ± 14.7 years) in a Hidaka cohort study. After a median follow-up period of 10.9 years, 160 participants had developed cancer. The Cox proportional hazards model was used to estimate quartile-specific HRs and 95% confidential intervals (CI) for cancer risk. After adjustment for potential cancer risk factors including age, sex, current smoking habit, alcohol use, physical activities, body mass index, plasma immunoreactive insulin, and non-high-density lipoprotein cholesterol levels, we found a significant association between R-SOD activity and an increased risk of cancer (HR, 1.61; 95% CI, 1.03-2.52; P = 0.037). In analyses conducted separately by sex, a significant association was found in men (HR, 2.49; 95% CI, 1.35-4.59; P = 0.003) but not women (HR, 1.46; 95% CI, 0.70-3.05; P = 0.320). After excluding participants who developed cancer within 5 years of the baseline survey, the association was more evident in men (HR, 4.64; 95% CI, 1.88-11.45; P = 0.001). We found no association with cancer risk in women (HR, 1.01; 95% CI, 0.39-2.65; P = 0.983). Increased R-SOD activities were associated with an increased risk of cancer, particularly in men in this population., Significance: Our study is the first to show that increased R-SOD activity is associated with a significantly higher cancer risk in men but not in women. Antioxidative enzymes such as SOD are essential for maintaining cellular redox balance. Their roles in cancer development and prevention are yet to be fully elucidated., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Proprotein convertase subtilisin/kexin type 9 inhibitors stabilize vulnerable plaque, reducing cardiovascular events. However, manual optical coherence tomography (OCT) analysis of drug efficacy is challenging because of signal attenuation within lipid plaques., Methods and Results: Twenty-four patients with thin-cap fibroatheroma were prospectively enrolled and randomized to receive alirocumab (75 mg every 2 weeks) plus rosuvastatin (10 mg/day) or rosuvastatin (10 mg/day) alone. OCT images at baseline and 36 weeks were analyzed manually and with artificial intelligence (AI)-aided software. AI-aided OCT analysis showed significantly greater percentage changes in the alirocumab+rosuvastatin vs. rosuvastatin-alone group in fibrous cap thickness (FCT; median [interquartile range] 212.3% [140.5-253.5%] vs. 88.6% [63.0-119.6%]; P=0.006) and lipid volume (median [interquartile range] -30.8% [-51.8%, -16.6%] vs. -2.1% [-21.6%, 4.3%]; P=0.015). Interobserver reproducibility for changes in minimum FCT and lipid index was relatively low for manual analysis (interobserver intraclass correlation coefficient [ICC] 0.780 and 0.499, respectively), but high for AI-aided analysis (interobserver ICC 0.999 and 1.000, respectively). Agreements between manual and AI-aided OCT analyses of FCT and the lipid index were acceptable (concordance correlation coefficients 0.859 and 0.833, respectively)., Conclusions: AI-aided OCT analysis objectively showed greater plaque stabilization of adding alirocumab to rosuvastatin. Our results highlight the benefits of a fully automated AI-assisted approach for assessing drug efficacy, offering greater objectivity in evaluating serial changes in plaque stability vs. conventional OCT assessment.

Aims: Several algorithms can differentiate inferior axis premature ventricular contractions (PVCs) originating from the right side and left side on 12-lead electrocardiograms (ECGs). However, it is unclear whether distinguishing the origin should rely solely on PVC or incorporate sinus rhythm (SR). We compared the dual-rhythm model (incorporating both SR and PVC) to the PVC model (using PVC alone) and quantified the contribution of each ECG lead in predicting the PVC origin for each cardiac rotation., Methods and Results: This multicentre study enrolled 593 patients from 11 centres-493 from Japan and Germany, and 100 from Belgium, which were used as the external validation data set. Using a hybrid approach combining a Resnet50-based convolutional neural network and a transformer model, we developed two variants-the PVC and dual-rhythm models-to predict PVC origin. In the external validation data set, the dual-rhythm model outperformed the PVC model in accuracy (0.84 vs. 0.74, respectively; P < 0.01), precision (0.73 vs. 0.55, respectively; P < 0.01), specificity (0.87 vs. 0.68, respectively; P < 0.01), area under the receiver operating characteristic curve (0.91 vs. 0.86, respectively; P = 0.03), and F1-score (0.77 vs. 0.68, respectively; P = 0.03). The contributions to PVC origin prediction were 77.3% for PVC and 22.7% for the SR. However, in patients with counterclockwise rotation, SR had a greater contribution in predicting the origin of right-sided PVC., Conclusion: Our deep learning-based model, incorporating both PVC and SR morphologies, resulted in a higher prediction accuracy for PVC origin, considering SR is particularly important for predicting right-sided origin in patients with counterclockwise rotation., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Stage B heart failure (HF) refers to structural heart disease without signs or symptoms of HF, so that early intervention may delay or prevent the onset of overt HF. However, stage B HF is a very broad concept, and risk stratification of such patients can be challenging., Methods and Results: We conducted a prospective study of data for 1646 consecutive patients with HF from the KUNIUMI (Kobe University Heart Failure Registry in Awaji Medical Center) registry chronic cohort. The definition of HF stages was based on current guidelines for classification of 29 patients as stage A HF, 761 as stage B HF, 827 as stage C HF, and 29 patients as stage D HF. The primary end point was the time-to-first-event defined as cardiovascular death or HF hospitalization within 2.0 years of follow-up. A maximum of 6 adjustment factor points was assigned based on Cox proportional hazards analysis findings for the hazard ratio (HR) of independent risk factors for the primary end point: 1 point for anemia, estimated glomerular filtration rate <45 mL/min per 1.73 m 2 , brain natriuretic peptide ≥150 pg/mL, and average ratio of early transmitral flow velocity to early diastolic mitral annular velocity >14, and 2 points for clinical frailty scale >3. Patients with stage B HF were stratified into 3 groups, low risk (0-1 points), moderate risk (2-3 points), and high risk (4-6 points). Based on this scoring system (BEEAF 2 [brain natriuretic peptide, estimated glomerular filtration rate, ratio of early transmitral flow velocity to early diastolic mitral annular velocity, anemia, and frailty]), the outcome was found to become worse in accordance with risk level. High-risk patients with stage B HF and patients with stage C HF showed similar outcomes., Conclusions: Our scoring system offers an easy-to-use evaluation of risk stratification for patients with stage B HF.

Introduction: Thermal atrial fibrillation (AF) ablation exerts an additive treatment effect on the cardiac autonomic nervous system (CANS). This effect is mainly reported during ablation of the right superior pulmonary vein (RSPV), modulating the right anterior ganglionated plexus (RAGP), which contains parasympathetic innervation to the sinoatrial node in the epicardial fat pad between RSPV and superior vena cava (SVC). However, a variable response to neuromodulation after ablation is observed, with little to no effect in some patients. Our objective was to assess clinical and anatomic predictors of thermal ablation-induced CANS changes, as assessed via variations in heart rate (HR) postablation., Methods: Consecutive paroxysmal AF patients undergoing first-time PV isolation by the cryoballoon (CB) or radiofrequency balloon (RFB) within a 12-month time frame and with preprocedural cardiac computed tomography (CT), were evaluated. Preablation and 24-h postablation electrocardiograms in sinus rhythm were collected and analyzed to assess HR. Anatomic evaluation by CT included the measurement of the shortest distance between the SVC and RSPV ostium (RSPV-SVC distance)., Results: A total of 97 patients (CB, n = 50 vs. RFB, n = 47) were included, with similar baseline characteristics between both groups. A significant HR increase postablation (ΔHR ≥ 15 bpm) occurred in a total of 37 patients (38.1%), without difference in number of patients between both thermal ablation technologies (CB, 19 [51%]), RFB, 18 [49%]). Independent predictors for increased HR were RSPV-SVC distance (odds ratio [OR]: 0.49, CI: 0.34-0.71, p value < .001), and age (OR: 0.94, CI: 0.89-0.98, p value = .003)., Conclusions: Thermal balloon-based PV isolation influences the CANS through its effect on the RAGP, especially in younger patients and patients with shorter RSPV-SVC distance., (© 2024 Wiley Periodicals LLC.)

Aims: Optical coherence tomography (OCT) can identify high-risk plaques indicative of worsening prognosis in patients with acute coronary syndrome (ACS). However, manual OCT analysis has several limitations. In this study, we aim to construct a deep-learning model capable of automatically predicting ACS prognosis from patient OCT images following percutaneous coronary intervention (PCI)., Methods and Results: Post-PCI OCT images from 418 patients with ACS were input into a deep-learning model comprising a convolutional neural network (CNN) and transformer. The primary endpoint was target vessel failure (TVF). Model performances were evaluated using Harrell's C -index and compared against conventional models based on human observation of quantitative (minimum lumen area, minimum stent area, average reference lumen area, stent expansion ratio, and lesion length) and qualitative (irregular protrusion, stent thrombus, malapposition, major stent edge dissection, and thin-cap fibroatheroma) factors. GradCAM activation maps were created after extracting attention layers by using the transformer architecture. A total of 60 patients experienced TVF during follow-up (median 961 days). The C -index for predicting TVF was 0.796 in the deep-learning model, which was significantly higher than that of the conventional model comprising only quantitative factors ( C -index: 0.640) and comparable to that of the conventional model, including both quantitative and qualitative factors ( C -index: 0.789). GradCAM heat maps revealed high activation corresponding to well-known high-risk OCT features., Conclusion: The CNN and transformer-based deep-learning model enabled fully automatic prognostic prediction in patients with ACS, with a predictive ability comparable to a conventional survival model using manual human analysis., Clinical Trial Registration: The study was registered in the University Hospital Medical Information Network Clinical Trial Registry (UMIN000049237)., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: A novel cardioprotective drug, vericiguat, reduces the risk of cardiovascular mortality for patients already on guideline-directed medical therapy. However, the effect of vericiguat on left ventricular (LV) reverse remodeling in patients with reduced LV ejection fraction (LVEF) with or without guideline-directed medical therapy, known as quadruple medical therapy, remains undetermined., Methods and Results: This study comprised 73 heart failure (HF) patients with reduced LVEF (<45%) from 5 institutions in Japan. Echocardiography was performed before and 6.1±3.9 months after administration of vericiguat. LV reverse remodeling was observed in all patients (LV end-diastolic volume 156.1±52.6 vs. 139.3±60.0 mL; P<0.001; LV end-systolic volume 108.1±41.2 vs. 91.8±51.2 mL; P<0.001; LVEF 31.8±7.4 vs. 37.6±12.3 %; P<0.001). LV reverse remodeling was also observed in 54 patients who could not undergo quadruple medical therapy for several reasons. Moreover, the incidence of cardiovascular events was also similar for patients who received or did not receive quadruple medical therapy (log-rank P=0.555)., Conclusions: Significant LV reverse remodeling was observed in HF patients with reduced LVEF following administration of vericiguat. LV reverse remodeling was also observed in patients who could not receive quadruple medical therapy, thus making administration of vericiguat a potential new approach for treatment of these patients., Competing Interests: H. Tanaka received remuneration from AstraZeneca plc, Ono Pharmaceutical Company, Limited. Pfizer Inc, Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Boehringer Ingelheim GmbH, Abbott Japan LLC, and Novartis International AG. K.H. has received research funding from Daiichi Sankyo Company, Limited, Actelion Pharmaceuticals Japan, Terumo Corporation, Abbott Vascular Japan, Otsuka Pharmaceutical Company, Limited, Kowa Company, Limited, Takeda Pharmaceutical Company Limited, Nihon Medi-Physics Company Limited, Novartis Pharma Company Limited, Bayer Company Limited, Biotronic Japan Company Limited, FUJIFILM Toyama Chemical Company Limited, Medtronic Japan Company Limited, Sysmex Company Limited. The remaining authors have no conflicts of interest to declare., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: Hemothorax caused by a right intercostal artery (ICA) injury behind the left atrium (LA) is a potentially fatal complication during pulmonary vein isolation. However, their anatomic relationship has not been fully elucidated., Objective: This study aimed to investigate the clinical anatomy of the right ICA in relation to the LA., Methods: This retrospective study included 100 patients (70.2 ± 10.6 years; 39.0% female) who underwent cardiac computed tomography. The patients were divided into sinus rhythm and atrial fibrillation groups. We focused on the distance between the LA and right ICAs and its predictive factors., Results: On average, 3.7 ± 0.7 right ICAs were found behind the LA. Of these, the eighth ICA was the closest in 54% of the cases, followed by the seventh ICA in 29% and the ninth ICA in 14%. The average closest distance between them was 3.8 ± 3.8 mm, which was significantly shorter in the atrial fibrillation group than in the sinus rhythm group (3.0 ± 3.2 mm vs 4.7 ± 4.2 mm; P = .006). Multivariate analysis revealed that a thinner chest cavity (β = -0.512; P = .002) and LA dilation (β = -0.432; P = .001) were predictors of shorter distance. The closest points distributed along the vertebral column, generally near the inferior pulmonary vein orifices., Conclusion: Right ICA-LA proximity was systematically clarified. Particularly in cases with an enlarged LA or thin chest cavity, operators should be aware of the potential risk of injuring the right ICA during pulmonary vein isolation., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt., (© 2024. The Author(s).)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the functional and structural effects of amyloid infiltration, predominantly within the ventricles, causing biventricular wall thickening. Amyloid infiltration can be observed in the left atrium in ATTR-CM patients, but the association of left atrial (LA) myocardial function with cardiovascular events and of changes in LA myocardial function with tafamidis administration have not yet been clarified. Our aim was, therefore, to use speckle-tracking strain for investigating LA myocardial function in patients with ATTR-CM treated with tafamidis. We studied 55 patients with biopsy-proven ATTR-CM who had been treated with tafamidis (age: 76 ± 2 years, male: 93%). For speckle-tracking analysis of LA myocardial function, the systolic LA strain (LA reservoir function) was defined for this study as LA myocardial function from the apical 4-chamber view. The primary endpoint was defined as a composite comprising cardiovascular death and/or heart failure hospitalization after tafamidis administration over a median follow-up period of 28 ± 4 months. Patients with baseline LA strain < 8.6% (median value) experienced significantly more cardiovascular events than those without (log-rank P = 0.002). Moreover, LA strain in 26 patients worsened after tafamidis administration, and multivariate logistic regression analysis showed age, global longitudinal strain and relative apical longitudinal strain index were identified as independent determinants of deterioration of LA strain after tafamidis administration. In conclusion, baseline LA reservoir function is closely associated with cardiovascular events after tafamidis administration, and could be an additional parameter for the management of patients with ATTR-CM., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background: Calcification score by cardiac computed tomography (CT) is required for diagnosis of paradoxical low-flow/low-gradient (PLFLG) aortic stenosis (AS). According to the guideline, velocity ratio (VR) < 0.25 by echocardiography is defined as severe AS, but utility of VR in patients with PLFLG AS remains unknown. This retrospective study was therefore conducted to investigate the utility of VR for a diagnosis of severe AS based on CT in patients with PLFLG AS., Methods: We studied 58 patients with PLFLG AS. Severity of AS was defined as calcium score derived from cardiac CT., Results: Of the 58 patients, 28 (48.3%) were diagnosed with severe AS based on CT, while 23 of them (82.1%) had VR < 0.25. It was noteworthy that receiver operating characteristic curve analysis showed that the optimal VR cutoff value for a diagnosis of severe AS was 0.25, with an area under the curve of 0.870 (P < 0.001). Sensitivity, specificity, positive predictive value, and negative predictive value of VR < 0.25 for a diagnosis of severe AS were 82.1%, 86.7%, 85.2% and 83.9%, respectively. Furthermore, patients who match the value of VR and severity of AS based on CT had higher prevalence of atrial fibrillation, higher serum brain natriuretic peptide concentration, larger left ventricular end-diastolic volume, and left ventricular stroke volume index., Conclusion: The measurement of VR is simple, and VR < 0.25 can be used for diagnosis of patients with PLFLG AS as severe. Our findings may thus have clinical implications for routine clinical practice., (© 2024. Japanese Society of Echocardiography.)

The 88 th Annual Scientific Meeting of the Japanese Circulation Society (JCS2024) was held from Friday, March 8 th to Sunday, March 10 th in Kobe, Japan. The main theme of this 3-day meeting was "The Future of Cardiology: Challenges in Overcoming Cardiovascular Disease". As COVID-19 has been finally conquered, with revision of its categorization under the Infectious Disease Control Law and relaxation of infection prevention measures, it was once again possible to have face-to-face presentations and lively discussion. JCS2024 was a major success, with 19,209 participants and attendees, thanks to the greatly appreciated cooperation and support from all affiliates.

Background: This prospective multicenter study assessed the prevalence of myocardial injury in patients with COVID-19 using cardiac magnetic resonance imaging (CMR)., Methods and Results: We prospectively screened 505 patients with moderate to severe COVID-19 disease from 7 hospitals in Japan. Of these patients, 31 (mean [±SD] age 63.5±10.4 years, 23 [74%] male) suspected of myocardial injury, based on elevated serum troponin or B-type natriuretic peptide concentrations either upon admission or 3 months after discharge, underwent CMR 3 months after discharge. The primary endpoint was the presence of myocardial injury, defined by any of the following: (1) contrast enhancement in the left or right ventricle myocardium on late gadolinium enhancement CMR; (2) left or right ventricular dysfunction (defined as <50% and <45%, respectively); and (3) pericardial thickening on contrast enhancement. The mean (±SD) duration between diagnosis and CMR was 117±16 days. The primary endpoint was observed in 13 of 31 individuals (42%), with 8 (26%) satisfying the modified Lake Louise Criteria for the diagnosis of acute myocarditis., Conclusions: This study revealed a high incidence of myocardial injury identified by CMR in patients with moderate to severe COVID-19 and abnormal findings for cardiac biomarkers.

Background: Combining morphological and physiological evaluations might improve the risk stratification of patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) culprit lesions., Aims: We aimed to investigate the clinical utility of morphofunctional evaluation after PCI for identifying ACS patients with increased risk of subsequent clinical events., Methods: We retrospectively studied 298 consecutive ACS patients who had undergone optical coherence tomography (OCT)-guided PCI. We performed OCT-based morphological analysis and quantitative flow ratio (QFR)-based physiological assessment immediately after PCI. The non-culprit segment (NCS) was defined as the most stenotic untreated segment in the culprit vessel. The primary outcome was target vessel failure (TVF), a composite of cardiac death, target vessel-related myocardial infarction, and ischaemia-driven target vessel revascularisation., Results: During a median follow-up period of 990 days, 42 patients experienced TVF. Cox regression analysis revealed that the presence of thin-cap fibroatheroma (TCFA) in the NCS and a low post-PCI QFR, or the presence of TCFA in the NCS and a high ΔQFR in the NCS (QFR NCS ), were independently associated with TVF. The subgroup with TCFA in the NCS and a low post-PCI QFR had a significantly higher incidence of TVF (75%) than the other subgroups, and those with TCFA in the NCS and a high ΔQFR NCS had a significantly higher incidence of TVF (86%) than the other subgroups. The integration of TCFA in NCS, post-PCI QFR, and ΔQFR NCS with traditional risk factors significantly enhanced the identification of subsequent TVF cases., Conclusions: Combining post-PCI OCT and QFR evaluation may enhance risk stratification for ACS patients after successful PCI, particularly in predicting subsequent TVF.

Background: Murray law-based quantitative flow ratio (μQFR) is a novel computational method that enables accurate estimation of fractional flow reserve (FFR) using a single angiographic projection. However, its diagnostic value in patients with severe aortic stenosis (AS) remains unclear., Method: We included 25 consecutive patients who underwent transcatheter aortic valve replacement (TAVR) for severe AS with intermediate or greater (30-90%) coronary artery disease (CAD). Pre- and post-TAVR μQFR, QFR, instantaneous flow reserve (iFR), and post-TAVR invasive FFR values were measured. We evaluated the diagnostic performance of pre-TAVR μQFR, QFR, and iFR using post-TAVR FFR ≤ 0.80 as a reference standard of ischemia., Result: Pre-TAVR μQFR was significantly correlated with post-TAVR FFR (r = 0.73, p < 0.0001). The area under the curve of pre-TAVR μQFR on post-TAVR FFR ≤ 0.8 was 0.91 (95% confidence interval [CI] 0.77-0.98), comparable to that of pre-TAVR iFR (0.86 [95% CI 0.71-0.98], p = 0.97). The accuracy, sensitivity, specificity, and positive and negative predictive values of pre-TAVR μQFR on post-TAVR FFR ≤ 0.8 were 84.2% (95% CI 68.7-93.4), 61.6% (95% CI 31.6-86.1), 96.0% (95% CI 79.6-99.9), 88.9% (95% CI 52.9-98.3), and 82.8% (95% CI 70.6-90.6), respectively. For pre-TAVR iFR, these values were 76.5% (95% CI 58.8-89.3), 90.9% (95% CI 58.7-99.8), 69.6% (95% CI 47.1-86.8), 58.8% (95% CI 42.8-73.1), and 94.1% (95% CI 70.8-99.1), respectively., Conclusion: μQFR could be useful for the physiological evaluation of patients with severe AS with concomitant CAD., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background: Anthracycline chemotherapy-related cardiac dysfunction is believed to be refractory to conventional pharmacological therapy and is associated with a poor prognosis. Increased heart rate (HR) is a known marker of cardiovascular outcomes for various categories of heart failure (HF). However, little interest has been expressed regarding increased HR after anthracycline chemotherapy. Aim of this study was to investigate the effect of increased HR soon after completion of anthracycline chemotherapy on subsequent left ventricular (LV) ejection fraction (LVEF) in cancer patients., Methods: We studied 172 patients with breast cancer and malignant lymphoma with preserved LVEF (≥ 50 %) and sinus rhythm treated with anthracyclines. Electrocardiography was performed before and soon after completion of anthracycline chemotherapy (2.3 months), and echocardiography before and late after completion of anthracycline chemotherapy (10.5 months)., Results: HR significantly increased from 74.2 ± 14.2 bpm to 75.9 ± 13.2 bpm (P = 0.05) soon after completion of anthracycline chemotherapy, while LVEF subsequently significantly decreased from 65.3 ± 5.5 % to 62.4 ± 6.1 % (P < 0.01) late after completion of anthracycline chemotherapy. Patients whose HR increased ≥10 bpm subsequently showed a significantly greater decrease in LVEF than those whose HR increased <10 bpm [-4.9 % (-32.7 % - 10.8 %) vs. -2.2 % (-21.2 % - 12.9 %), p = 0.04]. Multivariable logistic regression analysis showed that an increase in HR soon after completion of anthracycline chemotherapy was independently associated with a subsequent decrease in LVEF (odds ratio: 1.022, 95 % confidential interval; 1.008-1.037, P = 0.002)., Conclusions: Our findings may have a novel effect on the management of cancer patients scheduled for anthracycline chemotherapy., Competing Interests: Declaration of competing interest H.T. has received remuneration from AstraZeneca plc, Otsuka Pharmaceutical Company, Limited, Ono Pharmaceutical Company, Limited, Pfizer Inc., Daiichi Sankyo Company, Limited, and Novartis International AG. K.H. has received research funding from Daiichi Sankyo Company, Limited, Actelion Pharmaceuticals Japan, Terumo Corporation, Abbott Vascular Japan, Otsuka Pharmaceutical Company, Limited, Kowa Company, Limited, Takeda Pharmaceutical Company Limited, Nihon Medi-Physics Company Limited, Novartis Pharma Company Limited, Bayer Company Limited, Biotronic Japan Company Limited, FUJIFILM Toyama Chemical Company Limited, Medtronic Japan Company Limited, Sysmex Company Limited. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Although low high-density lipoprotein cholesterol (HDL-C) levels are a common metabolic abnormality associated with insulin resistance, their role in cardiovascular risk stratification remains controversial. Recently, we developed a simple, high-throughput, cell-free assay system to evaluate the "cholesterol uptake capacity (CUC)" as a novel concept for HDL functionality. In this study, we assessed the CUC in patients with hypertriglyceridemia and diabetes mellitus., Methods: The CUC was measured using cryopreserved serum samples from 285 patients who underwent coronary angiography or percutaneous coronary intervention between December 2014 and May 2019 at Kobe University Hospital., Results: The CUC was significantly lower in diabetic patients (n = 125) than in nondiabetic patients (93.0 vs 100.7 arbitrary units (A.U.), P = 0.002). Patients with serum triglyceride (TG) levels >150 mg/dL (n = 94) also had a significantly lower CUC (91.8 vs 100.0 A.U., P = 0.004). Furthermore, the CUC showed a significant inverse correlation with TG, hemoglobin A1c (Hb A1c), homeostasis model assessment of insulin resistance (HOMA-IR), and body mass index (BMI). Finally, the HDL-C/Apolipoprotein A1 (ApoA1) ratio, calculated as a surrogate index of HDL particle size, was significantly positively correlated with the CUC (r2 = 0.49, P < 0.001), but inversely correlated with TG levels (r2 = -0.30, P < 0.001)., Conclusions: The CUC decreased in patients with hypertriglyceridemia and diabetes mellitus, and HDL particle size was a factor defining the CUC and inversely correlated with TG levels, suggesting that impaired CUC in insulin-resistant states was partially due to the shift in HDL towards smaller particles. These findings provide a better understanding of the mechanisms underlying impaired HDL functionality., (Published by Oxford University Press on behalf of Association for Diagnostics & Laboratory Medicine 2024.)

There is no treatment for acute aortic dissection (AAD) targeting inflammatory cells. We aimed to identify the new therapeutic targets associated with inflammatory cells. We characterized the specific distribution of myeloid cells of both human type A AAD samples and a murine AAD model generated using angiotensin II (ANGII) and β-aminopropionitrile (BAPN) by single-cell RNA sequencing (scRNA-seq). We also examined the effect of an anti-interleukin-1β (IL-1β) antibody in the murine AAD model. IL1B + inflammatory macrophages and classical monocytes were increased in human AAD samples. Trajectory analysis demonstrated that IL1B + inflammatory macrophages differentiated from S100A8/9/12 + classical monocytes uniquely observed in the aorta of AAD. We found increased infiltration of neutrophils and monocytes with the expression of inflammatory cytokines in the aorta and accumulation of inflammatory macrophages before the onset of macroscopic AAD in the murine AAD model. In blocking experiments using an anti-IL-1β antibody, it improved survival of murine AAD model by preventing elastin degradation. We observed the accumulation of inflammatory macrophages expressing IL-1β in both human AAD samples and in a murine AAD model. Anti-IL-1β antibody could improve the mortality rate in mice, suggesting that it may be a treatment option for AAD., (© 2024. The Author(s).)

Competing Interests: Funding Support and Author Disclosures The Section of Arrhythmia is supported by an endowment from Abbott Japan, Boston Scientific Japan, and Medtronic Japan. Dr Hirata chairs the section, and Drs Fukuzawa and Imamura belong to the section. Dr Fukuzawa has received a scholarship donation from Biotronik Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Acute coronary syndrome (ACS) involves plaque-related thrombosis, causing primary ischemic cardiomyopathy or lethal arrhythmia. We previously demonstrated a unique immune landscape of myeloid cells in the culprit plaques causing ACS by using single-cell RNA sequencing. Here, we aimed to characterize T cells in a single-cell level, assess clonal expansion of T cells, and find a therapeutic target to prevent ACS., Methods: We obtained the culprit lesion plaques from 4 patients with chronic coronary syndrome (chronic coronary syndrome plaques) and the culprit lesion plaques from 3 patients with ACS (ACS plaques) who were candidates for percutaneous coronary intervention with directional coronary atherectomy. Live CD45 + immune cells were sorted from each pooled plaque samples and applied to the 10× platform for single-cell RNA sequencing analysis. We also extracted RNA from other 3 ACS plaque samples and conducted unbiased TCR (T-cell receptor) repertoire analysis., Results: CD4 + T cells were divided into 5 distinct clusters: effector, naive, cytotoxic, CCR7 + (C-C chemokine receptor type 7) central memory, and FOXP3 (forkhead box P3) + regulatory CD4 + T cells. The proportion of central memory CD4 + T cells was higher in the ACS plaques. Correspondingly, dendritic cells also tended to express more HLAs (human leukocyte antigens) and costimulatory molecules in the ACS plaques. The velocity analysis suggested the differentiation flow from central memory CD4 + T cells into effector CD4 + T cells and that from naive CD4 + T cells into central memory CD4 + T cells in the ACS plaques, which were not observed in the chronic coronary syndrome plaques. The bulk repertoire analysis revealed clonal expansion of TCRs in each patient with ACS and suggested that several peptides in the ACS plaques work as antigens and induced clonal expansion of CD4 + T cells., Conclusions: For the first time, we revealed single cell-level characteristics of CD4 + T cells in patients with ACS. CD4 + T cells could be therapeutic targets of ACS., Registration: URL: https://upload.umin.ac.jp/cgi-open-bin/icdr&#95;e/ctr&#95;view.cgi?recptno=R000046521; Unique identifier: UMIN000040747., Competing Interests: Disclosures None.

In Japan, cerebrovascular diseases and cardiovascular diseases (CVDs) are major causes of death and long-term care. Against this, the Cerebrovascular and Cardiovascular Disease Control Act was passed by a legislative body and promulgated in December 2018, and enacted on December 1, 2019. Based on the Japanese National Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease (Japanese National Plan), prefectural plans have been formulated and published from March 2021 to January 2023. Although the majority of individual measures were comprehensively articulated in accordance with the Japanese National Plan, some prefectures did not describe individual measures such as research, collection of medical information, consultation support for patients with CVD, palliative care, assistance for patients with sequelae, support for maintaining a balance between treatment and work, and measures from childhood and adolescence. Furthermore, a few specific indicators were set for these measures and those related to chronic care. This review identifies the current status of prefectural plans and discusses future challenges and directions.

Background: Detection of left ventricular (LV) abnormalities is essential for patients with preclinical heart failure (HF) to delay progression to clinical HF. Global longitudinal strain (GLS) is a sensitive marker for the early occurrence of subtle abnormalities in LV function, but not all echocardiographic instruments can measure GLS., Methods and results: We studied 853 preclinical HF patients to devise a scoring system for predicting low GLS (<16%). The associations of medical history and echocardiographic parameters with low GLS were evaluated using Cox proportional hazards analysis. Model 1 of the system consisted of medical history; for Model 2, conventional echocardiographic parameters were added to Model 1. For Model 1, a score ≥5 points meant prediction of low GLS with 90.2% sensitivity and 62.9% specificity (male=1 point, hypertension=4 points, dyslipidemia=1 point, atrial fibrillation=2 points, history of cardiac surgery=2 points). For Model 2, a score ≥4 points denotes prediction of low GLS with 80.3% sensitivity and 76.5% specificity (male=1 point, hypertension=2 points, atrial fibrillation=2 points, LV mass index >116 g/m 2 [male] or >96 g/m 2 [female]=1 point, LV ejection fraction <59%=2 points, E/e' >14=1 point)., Conclusions: Our scoring system provides an easy-to-use evaluation of LV longitudinal myocardial dysfunction, and may prove useful for risk stratification of patients with preclinical HF.

Background: Early detection and intervention for preclinical heart failure (HF) are crucial for restraining the potential increase in patients with HF. Thus, we designed and conducted a single-center retrospective cohort study to confirm the efficacy of B-type natriuretic peptide (BNP) for the early detection of preclinical HF in a primary care setting., Methods and results: We investigated 477 patients with no prior diagnosis of HF who were under the care of general practitioners. These patients were categorized into 4 groups based on BNP concentrations: Category 1, 0 pg/mL≤BNP≤35 pg/mL; Category 2, 35 pg/mL200 pg/mL. There was a marked and statistically significant increase in the prevalence of preclinical HF with increasing BNP categories: 19.9%, 57.9%, 87.5%, and 96.0% in Categories 1, 2, 3, and 4, respectively. Compared with Category 1, the odds ratio of preclinical HF in Categories 2, 3, and 4 was determined to be 5.56 (95% confidence interval [CI] 3.57-8.67), 23.70 (95% CI 8.91-63.11), and 171.77 (95% CI 10.31-2,861.93), respectively., Conclusions: Measuring BNP is a valuable tool for the early detection of preclinical HF in primary care settings. Proactive testing in patients at high risk of HF could play a crucial role in addressing the impending HF pandemic.

Background: Left ventricular (LV) longitudinal myocardial function is associated with the outcomes of heart failure (HF) patients. HF with improved ejection fraction (EF), known as HFimpEF, which is defined as current LVEF >40% but any previously documented LVEF ≤40%, has favorable outcomes compared with HF with preserved EF (HFpEF). However, LV longitudinal myocardial function in patients with previously reduced LVEF (<50%) but improved LVEF to within the normal range (≥50%) (HFnorEF) and its association with cardiovascular events remain unclear. Methods and Results: We studied 70 patients with HFpEF and 65 with HFnorEF. LV longitudinal myocardial function was assessed as global longitudinal strain (GLS). The primary endpoint was defined as cardiovascular death or HF hospitalization during follow-up of 5.6±3.1 years. The GLS of HFpEF patients was significantly lower than that of HFnorEF patients (13.6±3.5% vs. 14.8±2.2%, P=0.02) even when the LVEF was similar. Multivariate Cox proportional hazards analysis showed that GLS was independently associated with cardiovascular events. Furthermore, of the entire study population, patients with GLS >15.0% had fewer cardiovascular events than those without (log-rank P=0.014) among all the patients. Conclusions: LV longitudinal myocardial dysfunction was more frequently observed in patients with HFpEF than in those with HFnorEF, even when LVEF was similar, and was independently associated with cardiovascular events for HF patients with current LVEF ≥50%., Competing Interests: H.T. has received remuneration from AstraZeneca plc, Otsuka Pharmaceutical Company, Limited, Ono Pharmaceutical Company, Limited, Pfizer Inc., Daiichi Sankyo Company, Limited, and Novartis International AG. K.H. has received research funding from Daiichi Sankyo Company, Limited, Actelion Pharmaceuticals Japan, Terumo Corporation, Abbott Vascular Japan, Otsuka Pharmaceutical Company, Limited, Kowa Company, Limited, Takeda Pharmaceutical Company Limited, Nihon Medi-Physics Company Limited, Novartis Pharma Company Limited, Bayer Company Limited, Biotronic Japan Company Limited, FUJIFILM Toyama Chemical Company Limited, Medtronic Japan Company Limited, Sysmex Company Limited. The remaining authors have no conflicts of interest to declare., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Background: Recent guidelines discourage the use of pulmonary arterial hypertension (PAH)-targeted therapies in patients with pulmonary hypertension (PH) associated with respiratory diseases. Therefore, stratifications of the effectiveness of PAH-targeted therapies are important for this group., Objectives: The authors aimed to identify phenotypes that might benefit from initial PAH-targeted therapies in patients with PH associated with interstitial pneumonia and combined pulmonary fibrosis and emphysema., Methods: We categorized 270 patients with precapillary PH (192 interstitial pneumonia, 78 combined pulmonary fibrosis and emphysema) into severe and mild PH using a pulmonary vascular resistance of 5 WU. We investigated the prognostic factors and compared the prognoses of initial (within 2 months after diagnosis) and noninitial treatment groups, as well as responders (improvements in World Health Organization functional class, pulmonary vascular resistance, and 6-minute walk distance) and nonresponders., Results: Among 239 treatment-naive patients, 46.0% had severe PH, 51.8% had mild ventilatory impairment (VI), and 40.6% received initial treatment. In the severe PH with mild VI subgroup, the initial treatment group had a favorable prognosis compared with the noninitial treatment group. The response rate in this group was significantly higher than the others (48.2% vs 21.8%, ratio 2.21 [95% CI: 1.17-4.16]). In multivariate analysis, initial treatment was a better prognostic factor for severe PH but not for mild PH. Within the severe PH subgroup, responders had a favorable prognosis., Conclusions: This study demonstrated an increased number of responders to initial PAH-targeted therapy, with a favorable prognosis in severe PH cases with mild VI. A survival benefit was not observed in mild PH cases. (Multi-institutional Prospective Registry in Pulmonary Hypertension associated with Respiratory Disease; UMIN000011541)., Competing Interests: This study was supported by grants from Grant-in-Aid for Scientific Research (20FC1027, 23FC1031) from the Ministry of Health, Labour and Welfare of Japan, the Medical Research Fund of the Japan Medical Association (No. 16ek0109127h0002 and No. JP18lk1601003h0001), and the Nonprofit Organization Japan PH registry. Dr Tanabe has received remuneration from Nippon Shinyaku, Janssen Pharmaceutical K.K., and Bayer Yakuhin, and belongs to a department endowed by Nippon Shinyaku. Dr Kumamaru has received consultation fees from Mitsubishi-Tanabe Pharma Corp, and EPS Corp; speaker fee from Chugai Pharmaceutical Co, Ltd; and a research grant from Pfizer Japan Inc. Drs Kumamaru, Kinukawa, and Miyata are affiliated with the Department of Health Quality Assessment at the University of Tokyo, a social collaboration department supported by the National Clinical Database, Johnson & Johnson K.K., Nipro Corp, and Intuitive Surgical Sàrl. Dr Nishiyama has received remuneration from Nippon Shinyaku, Janssen Pharmaceutical K.K., and Boehringer Ingelheim. Dr Tsujino has received remuneration from Nippon Shinyaku and Janssen Pharmaceutical K.K., and belongs to a department endowed by Nippon Shinyaku, Mochida Pharmaceutical Co Ltd, Boehringer Ingelheim, Takeyama Co, Ltd, Kaneka Medics Co, and Medical System Network Co Ltd. Dr Inoue has received remuneration from Boehringer Ingelheim. Dr Hirata has received a research grant from Janssen Pharmaceutical K.K. Dr Kuwana has received remuneration from Nippon Shinyaku. Dr Handa has received a research grant from Fujifilm Corp and belongs to a department endowed by Teijin Pharma Ltd. Dr Taniguchi has received a research grant from Janssen Pharmaceutical K.K. Dr Matsubara has received remuneration from Nippon Shinyaku, Janssen Pharmaceutical K.K., Bayer Yakuhin, Mochida Pharmaceutical. Co Ltd, and Kaneka Medics Co; and research grants from Nippon Shinyaku, Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co Ltd, and Insmed Incorporated. Dr Tatsumi has received remuneration from Janssen Pharmaceutical K.K. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: We investigated the efficacy of left ventricular (LV) myocardial damage by native T 1 mapping obtained with cardiac magnetic resonance (CMR) for patients undergoing transcatheter edge-to-edge repair (TEER)., Methods and results: We studied 40 symptomatic non-ischemic heart failure (HF) patients and ventricular functional mitral regurgitation (VFMR) undergoing TEER. LV myocardial damage was defined as the native T 1 Z-score, which was converted from native T 1 values obtained with CMR. The primary endpoint was defined as HF rehospitalization or cardiovascular death over 12 months after TEER. Multivariable Cox proportional hazards analysis showed that the native T 1 Z-score was the only independent parameter associated with cardiovascular events (hazard ratio 3.40; 95% confidential interval 1.51-7.67), and that patients with native T 1 Z-scores <2.41 experienced significantly fewer cardiovascular events than those with native T 1 Z-scores ≥2.41 (P=0.001). Moreover, the combination of a native T 1 Z-score <2.41 and more severe VFMR (effective regurgitant orifice area [EROA] ≥0.30 cm 2 ) was associated with fewer cardiovascular events than a native T 1 Z-score ≥2.41 and less severe VFMR (EROA <0.30 cm 2 ; P=0.002)., Conclusions: Assessment of baseline LV myocardial damage based on native T 1 Z-scores obtained with CMR without gadolinium-based contrast media is a valuable additional parameter for better management of HF patients and VFMR following TEER.

Background: Fractional flow reserve-computed tomography (FFR CT ) has not been validated in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) for coronary artery disease due to theoretical difficulties in using nitroglycerin for such patients., Methods and results: In this single-center study, we prospectively enrolled 21 patients (34 vessels) and performed pre-TAVR FFR CT without nitroglycerin, pre-TAVR invasive instantaneous wave-free ratio (iFR) measurements, and post-TAVR FFR measurements using a pressure wire. The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of pre-TAVR FFR CT ≤0.80 to predict post-TAVR invasive FFR ≤0.80 were 82%, 83%, 82%, 71%, and 90%, respectively. A receiver operating characteristic analysis demonstrated an optimal cutoff of 0.78 for pre-TAVR FFR CT to indicate post-TAVR FFR ≤0.80, with an area under the curve (AUC) of 0.84, and the counterpart cutoff of pre-TAVR iFR was 0.89 with an AUC of 0.86., Conclusions: FFR CT without nitroglycerin could be a useful non-invasive imaging modality for assessing the severity of coronary artery lesions in patients with severe AS.

Stress has garnered significant attention as a prominent risk factor for inflammation-related diseases, particularly cardiovascular diseases (CVDs). However, the precise mechanisms underlying stress-driven CVDs remain elusive, thereby impeding the development of preventive and therapeutic strategies. To explore the correlation between plasma lipid metabolites and human depressive states, liquid chromatography-mass spectrometry (LC/MS) based analysis of plasma and the self-rating depression (SDS) scale questionnaire were employed. We also used a mouse model with restraint stress to study its effects on plasma lipid metabolites and stenotic vascular remodeling following carotid ligation. In vitro functional and mechanistic studies were performed using macrophages, endothelial cells, and neutrophil cells. We revealed a significant association between depressive state and reduced plasma levels of 4-oxoDHA, a specific omega-3 fatty acid metabolite biosynthesized by 5-lipoxygenase (LO), mainly in neutrophils. In mice, restraint stress decreased plasma 4-oxoDHA levels and exacerbated stenotic vascular remodeling, ameliorated by 4-oxoDHA supplementation. 4-oxoDHA enhanced Nrf2-HO-1 pathways, exerting anti-inflammatory effects on endothelial cells and macrophages. One of the stress hormones, noradrenaline, reduced 4-oxoDHA and the degraded 5-LO in neutrophils through the proteasome system, facilitated by dopamine D2-like receptor activation. Our study proposed circulating 4-oxoDHA levels as a stress biomarker and supplementation of 4-oxoDHA as a novel therapeutic approach for controlling stress-related vascular inflammation., (© 2024. The Author(s).)

Objective: The incidence of postoperative complications, including dysphagia, increases as the population undergoing cardiovascular surgery ages. This study aimed to explore the potential of maximum phonation time (MPT) as a simple tool for predicting postextubation dysphagia (PED) and major adverse cardiac and cerebrovascular events (MACCEs)., Methods: This retrospective study included 442 patients who underwent elective cardiac surgery at a university hospital. MPT was measured before surgery, and patients were stratified into 2 groups based on normal and abnormal MPTs. Postoperative complications, including PED and MACCEs, were also investigated. Swallowing status was assessed using the Food Intake Level Scale., Results: MPT predicted PED with prevalence of 11.0% and 18.0% in the normal and abnormal MPT groups, respectively ( P  = .01). During the follow-up period, MACCEs developed in 17.0% of patients. Frailty, European System for Cardiac Operative Risk Evaluation II score, PED, and MPT were markedly associated with MACCEs (adjusted hazard ratios: 2.25, 1.08, 1.96, and 0.96, respectively). Mediation analysis revealed that MPT positively influenced PED and MACCEs, whereas PED positively influenced MACCEs. The trend in restricted cubic spline analysis indicated that the hazard ratio for MACCEs increased sharply when MPT was <10 seconds., Conclusions: These findings underscore the potential of MPT as a valuable tool in the preoperative assessment and management of patients undergoing cardiac surgery. By incorporating MPT into routine preoperative evaluations, clinicians can identify patients at a higher risk of PED and MACCEs, allowing for targeted interventions and closer postoperative monitoring. This may improve patient outcomes and reduce the health care costs associated with these complications., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

Background: Perivascular inflammation contributes to the development of atherosclerosis and microcirculatory dysfunction. Pericoronary adipose tissue (PCAT) attenuation, measured by coronary computed tomography angiography, is a potential indicator of coronary inflammation. However, the relationship between PCAT attenuation, microcirculatory dysfunction, and periprocedural myocardial injury (PMI) remains unclear., Methods and Results: Patients with chronic coronary syndrome who underwent coronary computed tomography angiography before percutaneous coronary intervention were retrospectively identified. PCAT attenuation and adverse plaque characteristics were assessed using coronary computed tomography angiography. The extent of microcirculatory dysfunction was evaluated using the angio-based index of microcirculatory resistance before and after percutaneous coronary intervention. Overall, 125 consecutive patients were included, with 50 experiencing PMI (PMI group) and 75 without PMI (non-PMI group). Multivariable analysis showed that older age, higher angio-based index of microcirculatory resistance, presence of adverse plaque characteristics, and higher lesion-based PCAT attenuation were independently associated with PMI occurrence (odds ratio [OR], 1.07 [95% CI, 1.01-1.13]; P =0.02; OR, 1.06 [95% CI, 1.00-1.12]; P =0.04; OR, 6.62 [95% CI, 2.13-20.6]; P =0.001; and OR, 2.89 [95% CI, 1.63-5.11]; P <0.001, respectively). High PCAT attenuation was correlated with microcirculatory dysfunction before and after percutaneous coronary intervention and its exacerbation during percutaneous coronary intervention. Adding lesion-based PCAT attenuation to the presence of adverse plaque characteristics improved the discriminatory and reclassification ability in predicting PMI., Conclusions: Adding PCAT attenuation at the culprit lesion level to coronary computed tomography angiography-derived adverse plaque characteristics may provide incremental benefit in identifying patients at risk of PMI. Our results highlight the importance of microcirculatory dysfunction in PMI development, particularly in the presence of lesions with high PCAT attenuation., Registration: URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000057722; Unique identifier: UMIN000050662.

Sacubitril/valsartan has become an important first-line drug for symptomatic heart failure (HF) patients, especially with left ventricular (LV) ejection fraction (LVEF) < 50%. However, the impact of sacubitril/valsartan on cardiovascular outcomes, especially LV reverse remodeling for such patients with low blood pressure, remains uncertain. We retrospectively studied 164 HF patients with LVEF < 50% who were treated with sacubitril/valsartan from two institutions. Echocardiography was performed before and 9.5 ± 5.1 months after initiation of maximum tolerated dose of sacubitril/valsartan. The maximum tolerated dose of sacubitril/valsartan was lower for the low blood pressure group (≤ 100 mmHg in systole) than for the non-low blood pressure group (> 100 mmHg in systole) (165 ± 106 mg vs. 238 ± 124 mg, P = 0.017). As expected, significant LV reverse remodeling was observed in the non-low blood pressure group after initiation of sacubitril/valsartan. It was noteworthy that significant LV reverse remodeling was also observed in the low blood pressure group after initiation of sacubitril/valsartan (LV end-diastolic volume: 177.3 ± 66.0 mL vs. 137.7 ± 56.1 mL, P < 0.001, LV end-systolic volume: 131.6 ± 60.3 mL vs. 94.6 ± 55.7 mL, P < 0.001, LVEF: 26.8 ± 10.3% vs. 33.8 ± 13.6%, P = 0.015). Relative changes in LV volumes and LVEF after initiation of sacubitril/valsartan were similar for the two groups. In conclusion, significant LV reverse remodeling occurred after initiation of sacubitril/valsartan, even in HF patients with LVEF < 50% and systolic blood pressure ≤ 100 mmHg., (© 2023. Springer Nature Japan KK, part of Springer Nature.)

Background: Ultraviolet B (UV-B) irradiation is an effective treatment for human cutaneous disorders and was shown to reduce experimental atherosclerosis by attenuating immunoinflammatory responses. The aim of this study was to clarify the effect of specific wavelengths of UV-B on atherosclerosis and the underlying mechanisms focusing on immunoinflammatory responses., Methods and Results: Based on light-emitting diode technology, we developed novel devices that can emit 282 nm UV-B, which we do not receive from natural sunlight, 301 nm UV-B, and clinically available 312 nm UV-B. We irradiated 6-week-old male atherosclerosis-prone Apoe -/- (apolipoprotein E-deficient) mice with specific wavelengths of UV-B and evaluated atherosclerosis and immunoinflammatory responses by performing histological analysis, flow cytometry, biochemical assays, and liquid chromatography/mass spectrometry-based lipidomics. Irradiation of 282 nm UV-B but not 301 or 312 nm UV-B significantly reduced the development of aortic root atherosclerotic plaques and plaque inflammation. This atheroprotection was associated with specifically augmented immune responses of anti-inflammatory CD4 + Foxp3 (forkhead box P3) + regulatory T cells in lymphoid tissues, whereas responses of other immune cells were not substantially affected. Analysis of various lipid mediators revealed that 282 nm UV-B markedly increased the ratio of proresolving to proinflammatory lipid mediators in the skin., Conclusions: We demonstrated that 282 nm UV-B irradiation effectively reduces aortic inflammation and the development of atherosclerosis by systemically augmenting regulatory T-cell responses and modulating the balance between proresolving and proinflammatory lipid mediators in the skin. Our findings indicate that a novel 282 nm UV-B phototherapy could be an attractive approach to treat atherosclerosis.

Objectives: We previously reported a higher left atrial volume index (LAVI) was independently associated with left atrial (LA) appendage (LAA) thrombus formation in 737 patients with non-valvular atrial fibrillation (NVAF) receiving appropriate oral anticoagulation therapy. Since our previous study was a retrospective single-center study, we designed and conducted a prospective multi-center study to verify our findings for LAVI as a predictor of LAA thrombus in patients with NVAF receiving appropriate oral anticoagulation therapy., Methods: This prospective multi-center study comprised 746 consecutive patients with NVAF recruited between December 2021 and March 2023 from eight institutions in Japan, who were receiving appropriate oral anticoagulation therapy, had undergone transthoracic echocardiography and transesophageal echocardiography (TEE)., Results: LAA thrombi were observed in 21 patients (2.8%). The prevalence of LAA thrombus formation in patients with paroxysmal AF (PAF) was significantly lower than that in patients with non-PAF (0.7% vs. 4.1%, p = .006). LAA thrombus formation was detected in none (0/171) of the patients with normal size LA (LAVI ≤ 34 mL/m 2 ). The prevalence of LAA thrombus formation in patients with mildly dilated LA (LAVI: 34-49.9 mL/m 2 ) was 2.1% (6/283), but that in PAF patients was low at 1.0% (1/104). Furthermore, this prevalence in patients with severely dilated LA (LAVI ≥ 50 mL/m 2 ) was high at 5.1% (15/292)., Conclusions: The findings of this prospective multi-center study are consistent with those of our previous study. Thus, the need for TEE prior to catheter ablation or electrical cardioversion can be determined by the level of LAVI., (© 2024 Wiley Periodicals LLC.)

Alzheimer's disease (AD) is among the most prevalent age-related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its function in AD pathogenesis was unidentified. Here we created an AD mouse model with EC senescence (APP/PS1;TERF2DN mice) by intercrossing APP/PS1 mice with Tie2 promoter-driven dominant negative telomeric repeat-binding factor 2 transgenic mice (TERF2DN-Tg mice). We evaluated cognitive functions and AD brain pathology in APP/PS1;TERF2DN mice. Surprisingly, compared with the control APP/PS1 mice, APP/PS1;TERF2DN mice demonstrated the attenuation of cognitive impairment and amyloid-β (Aβ) pathology, accompanied by the compaction of Aβ plaques with increased microglial coverage and reduced neurite dystrophy. Moreover, we evaluated whether EC senescence could affect microglial morphology and phagocytosis of Aβ. Compared with wild-type mice, microglia in TERF2DN-Tg mice display increased numbers of endpoints (a morphometric parameter to quantify the number of processes) and Aβ phagocytosis and related gene expression. Single-cell RNA-sequencing analysis showed that compared with APP/PS1 mouse microglia, APP/PS1;TERF2DN mouse microglia displayed a modest decline in disease-associated microglia, accompanied by an altered direction of biological process branching from antigen synthesis and arrangement to ribonucleoprotein complex biogenesis. Our outcomes indicate that EC senescence alters microglia toward a protective phenotype with a rise in phagocytic and barrier roles, and may offer a clue to create a novel preventive/therapeutic method to treat AD., (© 2023 Wiley Periodicals LLC.)

Background: Diabetes increases the risk of heart failure (HF). 3-Hydroxyisobutyric acid (3-HIB) is a muscle-derived metabolite reflecting systemic insulin resistance. In this study, we investigated the prognostic impact of 3-HIB in patients with chronic HF., Methods and results: The KUNIUMI Registry chronic cohort is a community-based cohort study of chronic HF in Awaji Island, Japan. We analyzed the association between serum 3-HIB concentrations and adverse cardiovascular (CV) events in 784 patients from this cohort. Serum 3-HIB concentrations were significantly higher in patients with than without diabetes (P=0.0229) and were positively correlated with several metabolic parameters. According to Kaplan-Meier analysis, rates of CV death and HF hospitalization at 2 years were significantly higher among HF patients without diabetes in the high 3-HIB group (3-HIB concentrations above the median; i.e., >11.30 μmol/L) than in the low 3-HIB group (log-rank P=0.0151 and P=0.0344, respectively). Multivariable Cox proportional hazard models adjusted for established risk factors for HF revealed high 3-HIB as an independent predictor of CV death (hazard ratio [HR] 1.82; 95% confidence interval [CI] 1.16-2.85; P=0.009) and HF hospitalization (HR 1.72; 95% CI 1.17-2.53, P=0.006) in HF patients without diabetes, whereas no such trend was seen in subjects with diabetes., Conclusions: In a community cohort, circulating 3-HIB concentrations were associated with prognosis in chronic HF patients without diabetes.

Elevated circulating homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases (CVDs), including coronary artery disease (CAD) and heart failure (HF). It remains unclear how Hcy and its derivatives relate to left ventricular (LV) diastolic function. The aim of the present study was to investigate the relationship between plasma Hcy-related metabolites and diastolic dysfunction (DD) in patients with heart disease (HD). A total of 62 HD patients with preserved LV ejection fraction (LVEF ≥ 50%) were enrolled. Plasma Hcy and its derivatives were measured by liquid chromatography‒mass spectrometry (LC-MS/MS). Spearman's correlation test and multiple linear regression models were used to analyze the associations between metabolite levels and LV diastolic function. The cystine/methionine (CySS/Met) ratio was positively correlated with LV diastolic function, which was defined from the ratio of mitral inflow E and mitral e' annular velocities (E/e') (Spearman's r = 0.43, p < 0.001). When the subjects were categorized into two groups by E/e', the high-E/e' group had a significantly higher CySS/Met ratio than the low-E/e' group (p = 0.002). Multiple linear regression models revealed that the CySS/Met ratio was independently associated with E/e' after adjustment for age, sex, body mass index (BMI), diabetes mellitus, hypertension, chronic kidney disease (CKD),　hemoglobin, and lipid peroxide (LPO) {standardized β (95% CI); 0.14 (0.04-0.23); p = 0.005}. Hcy, CySS, and Met did not show a significant association with E/e' in the same models. A high plasma CySS/Met ratio reflected DD in patients with HD., (© 2023. Springer Nature Japan KK, part of Springer Nature.)

Background: There is a strong demand for remote monitoring systems to gather health data. This study investigated the safety, usefulness, and patient satisfaction in outpatient care using telehealth with real-time electrocardiogram (ECG) monitoring after catheter ablation. Methods and Results: In all, 38 patients who underwent catheter ablation were followed up using telehealth. At the 3- and 6-month follow-up, a self-fitted Duranta ECG monitoring device was sent to the patient's home before the online consultation. Patients attached the devices themselves, and the doctors viewed the patients by video chat and performed real-time ECG monitoring. The frequency of hospital visits and the ECG monitoring duration were compared with conventional in-person follow-up data (n=102). The completion rate for telehealth follow-up was 32 of 38 patients (84%). The number of hospital visits during the 6 months was significantly lower with telehealth follow-up than with conventional follow-up (median [interquartile range] 1 [1-1] vs. 5 [3-5]; P<0.0001). However, the ECG monitoring duration was approximately 4-fold longer for the telehealth follow-up (median [interquartile range] 89 [64-117] vs. 24 [0.1-24] h; P<0.0001). No major adverse events were observed during the telehealth follow-up. Patient surveys showed high satisfaction with telehealth follow-up due to reduced hospital visits. Conclusions: A combination of telehealth follow-up with real-time ECG monitoring increased the ECG monitoring duration and patient satisfaction without any adverse events., Competing Interests: The Section of Arrhythmia is supported by endowments from Abbott JAPAN, Medtronic JAPAN, and Boston Scientific JAPAN. The Section of Arrhythmia has received a scholarship fund from Biotronik JAPAN. K.H. chairs the Section, and K.F. and K.I. belong to the Section. However, none of the authors declare any conflicts of interest regarding this manuscript’s contents., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)

In acute lung injury (ALI), a severe insult induces a hyperinflammatory state in the lungs. The mortality rate of severe ALI remains high, and novel mechanistic insights are required to improve therapeutic strategies. Endothelin-2 (Edn2), the least studied isoform of endothelin, is involved in lung physiology and development and can be affected by various factors. One of them is inflammation, and another isoform of endothelin, endothelin-1 (Edn1), affects lung inflammatory responses. Considering the importance of Edn2 in the lungs and how Edn2 works through the same receptors as Edn1, we postulated that Edn2 may affect inflammatory responses that are central to ALI pathophysiology. In this study, we performed 24 hours intratracheal lipopolysaccharide (LPS) instillation or PBS control as an in vivo ALI model in eight-week-old conditional Edn2 knockout mice (Edn2-iKO), with Edn2-floxed mice as controls. Bronchoalveolar lavage (BAL) fluid and tissue were collected after exsanguination and analyzed for its cellular, molecular, functional, and histological inflammatory phenotypes. We found that Edn2-iKO mice displayed a reduced pro-neutrophilic inflammatory phenotype even after acute LPS treatment, shown by the reduction in the overall protein concentration and neutrophil count in bronchoalveolar lavage fluids. Further investigation revealed a reduction in mRNA interferon gamma (IFNγ) level of Edn2-iKO lungs and suppression of its downstream signaling, including phosphorylated level of STAT1 and IL-1β secretion, leading to reduced NFĸB activation. To conclude, Edn2 deletion suppressed acute lung inflammation by reducing neutrophil-mediated IFNγ/STAT1/IL-1β/NFĸB signaling cascade. Targeting Edn2 signaling may be beneficial for the development of novel treatment options for ALI.

Background: Global longitudinal strain (GLS) is reportedly a sensitive marker for early subtle abnormalities in left ventricular (LV) performance of asymptomatic patients with severe aortic stenosis (AS) and preserved LV ejection fraction (LVEF). For symptomatic patients with severe AS and preserved LVEF, however, the association of immediate improvement in GLS after transcatheter aortic valve implantation (TAVI) with long-term outcomes remains uncertain., Methods: This study concerned 151 symptomatic patients with severe AS and preserved LVEF who had undergone TAVI. Echocardiography was performed before TAVI and 7 (7-9) days after TAVI. GLS was determined by means of a two-dimensional speckle-tracking strain using current guidelines. The primary endpoint was defined as a composite endpoint comprising cardiovascular death or re-hospitalization for HF after TAVI over a median follow-up period of 27.7 (11.9-51.4) months., Results: Mean LVEF and GLS were 65 ± 7 % and 12.8 ± 3.4 %, respectively. The Kaplan-Meier curve indicated that patients with acute improvement in GLS after TAVI experienced fewer cardiovascular events than those without such improvement (log-rank P = 0.02). Multivariate analysis showed that non-acute improvement in GLS after TAVI was independently associated with worse outcomes as well as deterioration of the mean transaortic pressure gradient., Conclusion: Assessment of GLS immediately after TAVI is a valuable additional parameter for better management of symptomatic patients with severe AS and preserved LVEF who are scheduled for TAVI., Competing Interests: Conflict of interest H.T. is a consultant for AstraZeneca plc, Ono Pharmaceutical Company, Limited. Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, and Novartis International AG. H.O is a consultant for Abbott Vascular Japan and Terumo Co. K.H. has received research funding from Daiichi Sankyo Company, Limited, Actelion Pharmaceuticals Japan, Terumo Corporation, Abbott Vascular Japan, Otsuka Pharmaceutical Company, Limited, Kowa Company, Limited, Takeda Pharmaceutical Company Limited, Nihon Medi-Physics Company Limited, Novartis Pharma Company Limited, Bayer Company Limited, Biotronic Japan Company Limited, FUJIFILM Toyama Chemical Company Limited, Medtronic Japan Company Limited, Sysmex Company Limited. The remaining authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Drug-coated balloon (DCB) became a potential treatment option for patients with acute coronary syndrome (ACS); however, factors associated with target lesion failure (TLF) remain uncertain., Methods: This retrospective, multicentre, observational study included consecutive ACS patients who underwent optical coherence tomography (OCT)-guided DCB treatment. Patients were divided into two groups according to the occurrence of TLF, a composite of cardiac death, target vessel-related myocardial infarction, and ischemia-driven target lesion revascularisation., Results: We enrolled 127 patients in this study. During the median follow-up period of 562 (IQR: 342-1164) days, 24 patients (18.9%) experienced TLF, and 103 patients (81.1%) did not. The cumulative 3-year incidence of TLF was 22.0%. The cumulative 3-year incidence of TLF was the lowest in patients with plaque erosion (PE) (7.5%), followed by those with rupture (PR) (26.1%) and calcified nodule (CN) (43.5%). Multivariable Cox regression analysis revealed that plaque morphology was independently associated with TLF on pre-PCI (percutaneous coronary intervention) OCT, and residual thrombus burden (TB) was positively associated with TLF on post-PCI OCT. Further stratification by post-PCI TB revealed a comparable incidence of TLF in patients with PR (4.2%) to that of PE if the culprit lesion had a smaller post-PCI TB than the cut-off value (8.4%). TLF incidence was high in patients with CN, regardless of TB size on post-PCI OCT., Conclusions: Plaque morphology was strongly associated with TLF for ACS patients after DCB treatment. Residual TB post-PCI might be a key determinant for TLF, especially in patients with PR., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: Post-extubation dysphagia (PED), an often overlooked problem, is a common and serious complication associated with mortality and major morbidity after cardiovascular surgery. Dysphagia is considered an age-related disease, and evaluating its long-term effects is a pressing issue with rapidly progressing ageing worldwide. Therefore, we examined the effect of PED on functional status and long-term cardiovascular events in patients undergoing cardiovascular surgery., Methods and Results: This single-centre, retrospective cohort study included 712 patients who underwent elective cardiovascular surgery and met the inclusion criteria. Patients were divided into PED and non-PED groups based on their post-operative swallowing status. The swallowing status was assessed using the Food Intake Level Scale. Functional status was evaluated as hospital-associated disability (HAD), defined as a decrease in activities of daily living after hospital discharge compared with preoperative values. The patients were subsequently followed up to detect major adverse cardiac and cerebrovascular events (MACCEs). Post-extubation dysphagia was present in 23% of the 712 patients and was independently associated with HAD (adjusted odds ratio, 2.70). Over a 3.5-year median follow-up period, MACCE occurred in 14.1% of patients. Multivariate Cox proportional hazard analysis revealed HAD to be independently associated with an increased risk of MACCE (adjusted hazard ratio, 1.85), although PED was not significantly associated with MACCE., Conclusion: Post-extubation dysphagia was an independent HAD predictor, with the odds of HAD occurrence being increased by 2.7-fold due to PED. Hospital-associated disability accompanied by PED is a powerful predictor of poor prognosis. Perioperative evaluation and management of the swallowing status, and appropriate therapeutic interventions, are warranted., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Competing Interests: Funding Support and Author Disclosures The Section of Arrhythmia is supported by an endowment from Abbott Japan, Boston Scientific Japan, and Medtronic Japan. Dr Hirata chairs the Section, and Drs Fukuzawa and Takami belong to the Section. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Left atrial (LA) enlargement frequently occurs in atrial fibrillation (AF) patients, and this enlargement is associated with the development of heart failure, thromboembolism, or atrial functional mitral regurgitation (AFMR). AF patients can develop LA enlargement over time, but its progression depends on the individual. So far, the factors that cause progressive LA enlargement in AF patients have thus not been elucidated, so that the aim of this study was to identify the factors associated with the progression of LA enlargement in AF patients. We studied 100 patients with persistent or permanent AF (aged: 67 ± 2 years, 40 females). Echocardiography was performed at baseline and 12 (5-30) months after follow-up. LA size was evaluated as the LA volume index which was calculated with the biplane modified Simpson's method from apical four-and two-chamber views, and then normalized to the body surface area (LAVI). The deterioration of AFMR after follow-up was defined as a deterioration in severity of mitral regurgitation (MR) by a grade of 1 or more. Multivariate regression analysis demonstrated that hypertension (p = .03) was an independently associated parameter of progressive LA enlargement, as was baseline LAVI. In addition, the Kaplan-Meier curve indicated that patients with hypertension tended to show greater deterioration of AFMR after follow-up than those without hypertension (log-rank p = .08). Hypertension proved to be strongly associated with progression of LA enlargement over time in patients with AF. Our findings provide new insights for better management of patients with AF to prevent the development of AFMR., (© 2023 Wiley Periodicals LLC.)

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Section of Arrhythmia is supported by an endowment from Abbott JAPAN, Medtronic JAPAN, and Boston Scientific JAPAN. Ken-ichi Hirata chairs the Section, and Koji Fukuzawa and Mitsuru Takami belong to the Section. However, all authors report no conflict of interest for this manuscript's content.

This study determined the predictive accuracy of optical frequency domain imaging (OFDI) on debulking effects of rotational atherectomy (RA) and compared the predictive accuracy of OFDI catheter-based with Rota wire-based prediction methods. This prospective, single-center, observational study included 55 consecutive patients who underwent OFDI-guided RA. On pre-RA OFDI images, a circle, identical to the Rota burr was drawn at the center of the OFDI catheter (OFDI catheter-based prediction method) or wire (wire-based prediction method). The area overlapping the vessel wall was defined as the predicted ablation area (P-area). The actual ablated area (A-area) was measured by superimposing the OFDI images before and after RA. The overlapping P-area and A-area were defined as overlapped ablation area (O-area), and the predictive accuracy was evaluated by %Correct area (O-area/P-area) and %Error area (A-area  - O-area/A-area). The median %Correct and %Error areas were 47.8% and 41.6%, respectively. Irrelevant ablation (low %Correct-/high % Error areas) and over ablation (high %Correct-/high % Error areas) were related to deep vessel injury and intimal flap outside the P-area. The predictive accuracy was better in the OFDI catheter-based prediction method than the wire-based prediction method in the cross sections where the OFDI catheter and wire came in contact. However, it was better in the latter than the former where the OFDI catheter and wire were not in contact. OFDI-based simulation of the RA effect is feasible though accuracy may be affected by the OFDI catheter and wire position. OFDI-based simulation of RA effect might reduce peri-procedural complications during RA., (© 2023. The Author(s).)